{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,5]],"date-time":"2026-11-05T00:28:39Z","timestamp":1793838519741,"version":"4.6.1"},"reference-count":50,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"10","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2014,5,9]]},"abstract":"<jats:sec>\n                    <jats:title>\n                      <jats:underline>Rationale:<\/jats:underline>\n                    <\/jats:title>\n                    <jats:p>\n                      Healing after myocardial infarction involves the biphasic accumulation of inflammatory lymphocyte antigen 6C (Ly-6C)\n                      <jats:sup>high<\/jats:sup>\n                      and reparative Ly-6C\n                      <jats:sup>low<\/jats:sup>\n                      monocytes\/macrophages (Mo\/M\u03a6). According to 1 model, Mo\/M\u03a6 heterogeneity in the heart originates in the blood and involves the sequential recruitment of distinct monocyte subsets that differentiate to distinct macrophages. Alternatively, heterogeneity may arise in tissue from 1 circulating subset via local macrophage differentiation and polarization. The orphan nuclear hormone receptor, nuclear receptor subfamily 4, group a, member 1 (Nr4a1), is essential to Ly-6C\n                      <jats:sup>low<\/jats:sup>\n                      monocyte production but dispensable to Ly-6C\n                      <jats:sup>low<\/jats:sup>\n                      macrophage differentiation; dependence on Nr4a1 can thus discriminate between systemic and local origins of macrophage heterogeneity.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>\n                      <jats:underline>Objective:<\/jats:underline>\n                    <\/jats:title>\n                    <jats:p>This study tested the role of Nr4a1 in myocardial infarction in the context of the 2 Mo\/M\u03a6 accumulation scenarios.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>\n                      <jats:underline>Methods and Results:<\/jats:underline>\n                    <\/jats:title>\n                    <jats:p>\n                      We show that Ly-6C\n                      <jats:sup>high<\/jats:sup>\n                      monocytes infiltrate the infarcted myocardium and, unlike Ly-6C\n                      <jats:sup>low<\/jats:sup>\n                      monocytes, differentiate to cardiac macrophages. In the early, inflammatory phase of acute myocardial ischemic injury, Ly-6C\n                      <jats:sup>high<\/jats:sup>\n                      monocytes accrue in response to a brief C\u2013C chemokine ligand 2 burst. In the second, reparative phase, accumulated Ly-6C\n                      <jats:sup>high<\/jats:sup>\n                      monocytes give rise to reparative Ly-6C\n                      <jats:sup>low<\/jats:sup>\n                      F4\/80\n                      <jats:sup>high<\/jats:sup>\n                      macrophages that proliferate locally. In the absence of Nr4a1, Ly-6C\n                      <jats:sup>high<\/jats:sup>\n                      monocytes express heightened levels of C\u2013C chemokine receptor 2 on their surface, avidly infiltrate the myocardium, and differentiate to abnormally inflammatory macrophages, which results in defective healing and compromised heart function.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>\n                      <jats:underline>Conclusions:<\/jats:underline>\n                    <\/jats:title>\n                    <jats:p>\n                      Ly-6C\n                      <jats:sup>high<\/jats:sup>\n                      monocytes orchestrate both inflammatory and reparative phases during myocardial infarction and depend on Nr4a1 to limit their influx and inflammatory cytokine expression.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circresaha.114.303204","type":"journal-article","created":{"date-parts":[[2014,3,13]],"date-time":"2014-03-13T21:17:38Z","timestamp":1394745458000},"page":"1611-1622","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":559,"title":["Ly-6C\n                    <sup>high<\/sup>\n                    Monocytes Depend on Nr4a1 to Balance Both Inflammatory and Reparative Phases in the Infarcted Myocardium"],"prefix":"10.1161","volume":"114","author":[{"given":"Ingo","family":"Hilgendorf","sequence":"first","affiliation":[{"name":"From the Center for Systems Biology (I.H., L.M.S.G., C.W., B.G.C., Y.I., M.N., R.W., F.K.S.) and Department of Cardiology (T.C.T., M.S.-C.), Massachusetts General Hospital, Boston; Department of Gastroenterology, Hepatology, and Infectious Diseases, University of Duesseldorf, Duesseldorf, Germany (T.A.W.H.); Department of Medicine (R.L.) and Cardiovascular Division, Department of Medicine (P.L.), Brigham and Women\u2019s Hospital, Boston, MA; Department of Cardiology and Angiology I, University Heart..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louisa M.S.","family":"Gerhardt","sequence":"additional","affiliation":[{"name":"From the Center for Systems Biology (I.H., L.M.S.G., C.W., B.G.C., Y.I., M.N., R.W., F.K.S.) and Department of Cardiology (T.C.T., M.S.-C.), Massachusetts General Hospital, Boston; Department of Gastroenterology, Hepatology, and Infectious Diseases, University of Duesseldorf, Duesseldorf, Germany (T.A.W.H.); Department of Medicine (R.L.) and Cardiovascular Division, Department of Medicine (P.L.), Brigham and Women\u2019s Hospital, Boston, MA; Department of Cardiology and Angiology I, University Heart..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy C.","family":"Tan","sequence":"additional","affiliation":[{"name":"From the Center for Systems Biology (I.H., L.M.S.G., C.W., B.G.C., Y.I., M.N., R.W., F.K.S.) and Department of Cardiology (T.C.T., M.S.-C.), Massachusetts General Hospital, Boston; Department of Gastroenterology, Hepatology, and Infectious Diseases, University of Duesseldorf, Duesseldorf, Germany (T.A.W.H.); Department of Medicine (R.L.) and Cardiovascular Division, Department of Medicine (P.L.), Brigham and Women\u2019s Hospital, Boston, MA; Department of Cardiology and Angiology I, University Heart..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carla","family":"Winter","sequence":"additional","affiliation":[{"name":"From the Center for Systems Biology (I.H., L.M.S.G., C.W., B.G.C., Y.I., M.N., R.W., F.K.S.) and Department of Cardiology (T.C.T., M.S.-C.), Massachusetts General Hospital, Boston; Department of Gastroenterology, Hepatology, and Infectious Diseases, University of Duesseldorf, Duesseldorf, Germany (T.A.W.H.); Department of Medicine (R.L.) and Cardiovascular Division, Department of Medicine (P.L.), Brigham and Women\u2019s Hospital, Boston, MA; Department of Cardiology and Angiology I, University Heart..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tobias A.W.","family":"Holderried","sequence":"additional","affiliation":[{"name":"From the Center for Systems Biology (I.H., L.M.S.G., C.W., B.G.C., Y.I., M.N., R.W., F.K.S.) and Department of Cardiology (T.C.T., M.S.-C.), Massachusetts General Hospital, Boston; Department of Gastroenterology, Hepatology, and Infectious Diseases, University of Duesseldorf, Duesseldorf, Germany (T.A.W.H.); Department of Medicine (R.L.) and Cardiovascular Division, Department of Medicine (P.L.), Brigham and Women\u2019s Hospital, Boston, MA; Department of Cardiology and Angiology I, University Heart..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin G.","family":"Chousterman","sequence":"additional","affiliation":[{"name":"From the Center for Systems Biology (I.H., L.M.S.G., C.W., B.G.C., Y.I., M.N., R.W., F.K.S.) and Department of Cardiology (T.C.T., M.S.-C.), Massachusetts General Hospital, Boston; Department of Gastroenterology, Hepatology, and Infectious Diseases, University of Duesseldorf, Duesseldorf, Germany (T.A.W.H.); Department of Medicine (R.L.) and Cardiovascular Division, Department of Medicine (P.L.), Brigham and Women\u2019s Hospital, Boston, MA; Department of Cardiology and Angiology I, University Heart..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshiko","family":"Iwamoto","sequence":"additional","affiliation":[{"name":"From the Center for Systems Biology (I.H., L.M.S.G., C.W., B.G.C., Y.I., M.N., R.W., F.K.S.) and Department of Cardiology (T.C.T., M.S.-C.), Massachusetts General Hospital, Boston; Department of Gastroenterology, Hepatology, and Infectious Diseases, University of Duesseldorf, Duesseldorf, Germany (T.A.W.H.); Department of Medicine (R.L.) and Cardiovascular Division, Department of Medicine (P.L.), Brigham and Women\u2019s Hospital, Boston, MA; Department of Cardiology and Angiology I, University Heart..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronglih","family":"Liao","sequence":"additional","affiliation":[{"name":"From the Center for Systems Biology (I.H., L.M.S.G., C.W., B.G.C., Y.I., M.N., R.W., F.K.S.) and Department of Cardiology (T.C.T., M.S.-C.), Massachusetts General Hospital, Boston; Department of Gastroenterology, Hepatology, and Infectious Diseases, University of Duesseldorf, Duesseldorf, Germany (T.A.W.H.); Department of Medicine (R.L.) and Cardiovascular Division, Department of Medicine (P.L.), Brigham and Women\u2019s Hospital, Boston, MA; Department of Cardiology and Angiology I, University Heart..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Zirlik","sequence":"additional","affiliation":[{"name":"From the Center for Systems Biology (I.H., L.M.S.G., C.W., B.G.C., Y.I., M.N., R.W., F.K.S.) and Department of Cardiology (T.C.T., M.S.-C.), Massachusetts General Hospital, Boston; Department of Gastroenterology, Hepatology, and Infectious Diseases, University of Duesseldorf, Duesseldorf, Germany (T.A.W.H.); Department of Medicine (R.L.) and Cardiovascular Division, Department of Medicine (P.L.), Brigham and Women\u2019s Hospital, Boston, MA; Department of Cardiology and Angiology I, University Heart..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marielle","family":"Scherer-Crosbie","sequence":"additional","affiliation":[{"name":"From the Center for Systems Biology (I.H., L.M.S.G., C.W., B.G.C., Y.I., M.N., R.W., F.K.S.) and Department of Cardiology (T.C.T., M.S.-C.), Massachusetts General Hospital, Boston; Department of Gastroenterology, Hepatology, and Infectious Diseases, University of Duesseldorf, Duesseldorf, Germany (T.A.W.H.); Department of Medicine (R.L.) and Cardiovascular Division, Department of Medicine (P.L.), Brigham and Women\u2019s Hospital, Boston, MA; Department of Cardiology and Angiology I, University Heart..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine C.","family":"Hedrick","sequence":"additional","affiliation":[{"name":"From the Center for Systems Biology (I.H., L.M.S.G., C.W., B.G.C., Y.I., M.N., R.W., F.K.S.) and Department of Cardiology (T.C.T., M.S.-C.), Massachusetts General Hospital, Boston; Department of Gastroenterology, Hepatology, and Infectious Diseases, University of Duesseldorf, Duesseldorf, Germany (T.A.W.H.); Department of Medicine (R.L.) and Cardiovascular Division, Department of Medicine (P.L.), Brigham and Women\u2019s Hospital, Boston, MA; Department of Cardiology and Angiology I, University Heart..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Libby","sequence":"additional","affiliation":[{"name":"From the Center for Systems Biology (I.H., L.M.S.G., C.W., B.G.C., Y.I., M.N., R.W., F.K.S.) and Department of Cardiology (T.C.T., M.S.-C.), Massachusetts General Hospital, Boston; Department of Gastroenterology, Hepatology, and Infectious Diseases, University of Duesseldorf, Duesseldorf, Germany (T.A.W.H.); Department of Medicine (R.L.) and Cardiovascular Division, Department of Medicine (P.L.), Brigham and Women\u2019s Hospital, Boston, MA; Department of Cardiology and Angiology I, University Heart..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Nahrendorf","sequence":"additional","affiliation":[{"name":"From the Center for Systems Biology (I.H., L.M.S.G., C.W., B.G.C., Y.I., M.N., R.W., F.K.S.) and Department of Cardiology (T.C.T., M.S.-C.), Massachusetts General Hospital, Boston; Department of Gastroenterology, Hepatology, and Infectious Diseases, University of Duesseldorf, Duesseldorf, Germany (T.A.W.H.); Department of Medicine (R.L.) and Cardiovascular Division, Department of Medicine (P.L.), Brigham and Women\u2019s Hospital, Boston, MA; Department of Cardiology and Angiology I, University Heart..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralph","family":"Weissleder","sequence":"additional","affiliation":[{"name":"From the Center for Systems Biology (I.H., L.M.S.G., C.W., B.G.C., Y.I., M.N., R.W., F.K.S.) and Department of Cardiology (T.C.T., M.S.-C.), Massachusetts General Hospital, Boston; Department of Gastroenterology, Hepatology, and Infectious Diseases, University of Duesseldorf, Duesseldorf, Germany (T.A.W.H.); Department of Medicine (R.L.) and Cardiovascular Division, Department of Medicine (P.L.), Brigham and Women\u2019s Hospital, Boston, MA; Department of Cardiology and Angiology I, University Heart..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Filip K.","family":"Swirski","sequence":"additional","affiliation":[{"name":"From the Center for Systems Biology (I.H., L.M.S.G., C.W., B.G.C., Y.I., M.N., R.W., F.K.S.) and Department of Cardiology (T.C.T., M.S.-C.), Massachusetts General Hospital, Boston; Department of Gastroenterology, Hepatology, and Infectious Diseases, University of Duesseldorf, Duesseldorf, Germany (T.A.W.H.); Department of Medicine (R.L.) and Cardiovascular Division, Department of Medicine (P.L.), Brigham and Women\u2019s Hospital, Boston, MA; Department of Cardiology and Angiology I, University Heart..."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_5_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(12)61728-0"},{"key":"e_1_3_5_3_2","volume-title":"The Global Economic Burden of Noncommunicable Diseases","author":"Bloom DE","year":"2011","unstructured":"Bloom DE, Cafiero ET, Jane-Llopis E, Abrahams-Gessel S, Bloom LR, Fathima S, Feigl AB, Gaziano T, Mowafi M, Pandya A, Prettner K, Rosenberg L, Seligman B, Stein AZ, Weinstein CThe Global Economic Burden of Noncommunicable Diseases. 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